Ras, a product of ras oncogene, is a low-molecular-weight G protein, which consists of three Ras isoforms, H-Ras, N-Ras and K-Ras, in mammals. Since, constitutive activation of Ras function by the mutations of any of H-Ras, N-Ras and K-Ras is observed in human cancers with a high frequency, Ras is considered to be an eligible molecular target for development of anti-cancer drugs.
Ras controls signal transduction by cycling between GTP-bound active Ras (Ras-GTP) and GDP-bound inactive Ras (Ras-GDP) forms. In response to the binding of ligands (extracellular signal) such as cell growth factors to the receptors in cell membrane, Ras-GDP is activated by exchanging its GDP to GTP, and the resulting Ras-GTP transmits cell growth signals via binding to target molecules. Then, Ras-GTP is converted to Ras-GDP by the action of the factors (GTPase-activating proteins: GAPs) which promote intrinsic GTP hydrolysis (GTPase) activity of Ras, and the resulting Ras-GDP holds its inactive form until the next extracellular signal stimulation. In human cancers, the intrinsic GTP hydrolysis activity of Ras is impaired by Ras mutations (the active-form mutations). Further, the resulting mutants are unresponsive to the GTP hydrolysis-promoting action by GAPs, leading to abundance of an active form, Ras-GTP, in cells. Consequently, Ras continues to transmit cell growth signals leading to cancer development.
Since a Ras function inhibitor is a promising candidate as anticancer drug, its development has been desired. Farnesyl transferase inhibitors (FTIs) (Non-Patent Documents 1-4), which inhibit post translational lipid modification farnesylation of Ras, have been developed as a Ras function inhibitor. However, since they could not prolong the survival period of the drug-treated cancer patients, their development has been brought to a halt. At present, there is no effective therapeutic agent (drug) in the world.
Since the ratio of GTP-bound form in a cell is increased by Ras mutation in a human cancer, Ras-GTP is considered to be the most promising target for development of a Ras function inhibitor.
As compounds having a structure similar to that of the compounds described in the present specification, for example, compounds having a thioxothiazolidine skeleton are disclosed in Patent Documents 1 to 12. However, none of these documents disclose that such compound is a Ras function inhibitor.